A nucleoside-based supramolecular hydrogel integrating localized self-delivery and immunomodulation for periodontitis treatment.

Periodontitis is a highly prevalent oral disease characterized by bacterial-induced hyperactivation of the host immune system, leading to a sustained inflammatory response and osteoclastic activity, which ultimately results in periodontal destruction. In this work, an immunomodulatory supramolecular hydrogel for the topical treatment of periodontitis was synthesized using a simple one-pot method. This phenylboronate ester-based 8AGPB hydrogel exhibited excellent stability, self-healing properties, injectability, and biocompatibility. During degradation, the 8AGPB hydrogel releases immunomodulatory agent 8-aminoguanosine (8AG), which regulates MAPK and NF-κB signaling pathways by modulation of second messengers in macrophages. In combination with 1,4-phenylenediboronic acid (PBA), which possesses antioxidant properties, 8AG effectively inhibits ROS production and oxidative damage in LPS-stimulated macrophages, lowering the M1/M2 macrophage polarization ratio and reducing the secretion of pro-inflammatory factors. In an experimental periodontitis model using C57BL/6 mice, periodontal injection of the 8AGPB hydrogel reduced inflammatory infiltration and osteoclastic activity through immunomodulation and inhibition of osteoclast differentiation, thereby ameliorating periodontal destruction during periodontitis progression. Overall, the 8AGPB supramolecular hydrogel, serving as an injectable self-delivery platform for 8AG, may represent a promising novel strategy for periodontitis treatment and offer insights for the development of future topical anti-inflammatory systems.